This present invention relates to a novel composition containing an acid-labile benzimidazole, and to its preparation. This novel composition is perfectly suitable for oral administration. The invention also relates to a process for preparing this composition.
Many substances, of pharmaceutical value, that are labile in an acid medium have been described in the literature. The substances disclosed in the following patents can be given by way of example: EP 244 380, U.S. Pat. No. 4,045,563, EP-0 005 129, BE-898 880, GB-2 141 429, EP-0 146 370, GB-2 082 580, EP-A-0 173 664, EP-A-0 080 602, EP-0127 763, EP-0 134 400, EP-0 130 729, EP-0 150 586, DE-34 15971, GB-2 082 580, SE-A-8504048-3 and U.S. Pat. No. 4,182,766. On the other hand, omeprazole, which is of the family of benzimidazoles, corresponding to an anti-ulcer substance, used conventionally for decreasing gastrointestinal acid secretion, is well known and has been notably discussed in Swedish patent application 78.04231 filed on April 14, 1978, as well as in numerous other patents. Pantoprazole and lansoprazole which both correspond to anti-ulcer substances of the omeprazole family, are notably discussed in U.S. Pat. No. 4,758,579 and in U.S. Pat. No. 4,628,098 respectively.
Chemical substances that are easily destroyed in an acid medium (which is expressed herein by the term "acid-labile, and meaning chemical substances that are labile in an acid medium), such as benzimidazoles and, in particular, omeprazole, lansoprazole and pantoprazole, create a special problem for formulators when it is required to provide a pharmaceutical form designed for oral administration. The product does indeed come into contact with the stomach content, which is a highly acid medium, leading to breakdown of these chemical substances.
In order to avoid contact between the substances and the acid gastric juice following oral administration of the substance, a pharmaceutical formulation is conventionally used, such as a capsule or tablet which contains a core (tablet, microgranule, pellet, etc . . . ) containing the acid-labile active substance and an outer layer that surrounds this core and which consists of a gastro-resistant composition that is entero-soluble. Generally, the coating agent is a compound that is particularly insoluble in an acid medium, but which is soluble in a neutral or alkaline medium.
For substances that are highly labile in an acid medium but which are more stable in a neutral or alkaline medium, such as omeprazole, pantoprazole and lansoprazole, it is necessary to add an inert substance to the composition, which leads to an alkaline reaction aimed at improving stability of the active substance during manufacture thereof, and during storage of the pharmaceutical form.
Several prior art documents describe such compositions that are suitable for oral administration of acid-labile substances.
EP-0,244,380 discloses pharmaceutical formulations that are suitable for oral administration of acid-labile substances. It is stated that these acid-labile substances intended for oral administration must be protected by an enteric coating, but conventional enteric coatings of an acid nature are not suitable for this purpose. If one were indeed to cover acid-labile substances which such coatings, the substance would be rapidly decomposed due to direct or indirect contact with the coating, which manifests itself by a change of color and a decrease in the active substance content with the passage of time. The solution proposed in that patent corresponds to formulations consisting of: (a) a core in the form of small particles, i.e. pellets or compressed powder, containing the active substance along with an alkaline reacting compound, (b) one or several inert intermediate layers containing excipients for tablets which are soluble, and which rapidly disintegrate in water, water-soluble film-forming polymer compounds optionally containing alkaline compounds acting as a pH buffer between the core having an alkaline reaction and the outer layer, and (c) an outer layer consisting of an enteric composition. It is also stated that, in order to improve storage stability, the cores containing the active substance should also contain constituents having an alkaline reaction, and that the water that enters by diffusion, or the gastric juice, will dissolve part of the core close to the enteric coating, forming an alkaline solution at this level inside the coated form for administration. This patent claims pharmaceutical formulations containing acid-labile active substances of formula I with the notable exception of omeprazole.
EP-A-0,247,983 which is related to pharmaceutical formulations that are suitable for oral administration of acid-labile substances adopts the general principles developed in EP-A-0,244,380 in order to more particularly apply them to the case of omeprazole. The main claim in that application thus covers the association of omeprazole with an auxiliary alkaline-reacting substance.
U.S. Pat. No. 4,786,505 discloses novel stable preparations containing omeprazole intended for oral administration, their preparation and a method for treating gastrointestinal sicknesses using these novel preparations.
These oral pharmaceutical preparations comprise: (a) a core comprising omeprazole and an alkaline reacting compound, an alkaline salt of omeprazole and an alkaline-reacting compound or an alkaline salt of omeprazole alone; (b) at least one inert intermediate layer that is water-soluble or rapidly disintegrates in water; and (c) an external layer comprising an enteric coating.
EP-A-0,519,365 discloses pharmaceutical formulations that are suitable for oral administration of pantoprazole, comprising an acid-labile substance. In order to improve stability of pantoprazole formulations, this document discloses the use of the active substance in a salt form. The pharmaceutical formulations disclosed comprise: (a) a core containing the active principle in a salt form, (b) at least one water-soluble intermediate layer and (c) an outer layer corresponding to an enteric coating. It is stated that the use of a salt form in the core enables an alkaline environment to be created that protects the active substance. If the salt form does not have a sufficient effect on the pH, it is necessary to add a constituent that has an alkaline reaction to the core.
EP-A-0,519,144 discloses a novel process for producing a stable preparation containing omeprazole, intended for oral administration. This document notably discloses a process for preparing pellets containing omeprazole in which a core constituted of inert substances is covered by the active substance in finely divided form and dispersed in an aqueous dispersion buffered to a pH of 7.0, after which an enteric coating is applied, the finished product being placed inside a capsule.
U.S. Pat. No. 5,232,706 discloses novel stable pharmaceutical preparations containing omeprazole, intended for oral administration. The pharmaceutical compositions disclosed comprised: (a) a core containing omeprazole and an alkaline salt of omeprazole mixed with a first alkaline-reacting compound; (b) at least one intermediate layer formed by an excipient and a second alkaline-reacting compound and (c) an outer layer formed by an enteric coating. It is stated that the problem of the poor stability of the omeprazole is resolved, firstly, by increasing the way the core behaves as a base either by introducing omeprazole in the form of an alkali metal or alkaline-earth salt, or a mixture of omeprazole with a basic compound or by a combination of these two possibilities; and secondly "by incorporating an intermediate layer between the core and the enteric coating for preventing the alkaline core from causing breakdown of the enteric coating".
FR-A-2,692,146 discloses stable compositions of microgranules of gastro-protected omeprazole as well as their preparation. This documents particularly discloses a stable microgranule formulation of omeprazole comprising a neutral core consisting of sugar and starch covered with an active layer constituted by omeprazole diluted in mannitol in substantially equal amounts, and an intermediate layer comprising mannitol;an outer layer formed from an enteric coating being optionally present. There, it is indicated that the omeprazole is employed in a diluted powder form in an amount that is substantially equal to the amount of mannitol in order to protect the omeprazole from contact with solvents and with traces of water present in the binder solutions employed for applying the mixture of omeprazole and mannitol to the neutral grains consisting of sugar and starch. Additionally, according to that patent, supplementary protection of the omeprazole applied to neutral grains is obtained by means of a second protective layer consisting of mannitol and a binder solution in order to definitively isolate the core onto which the omeprazole and the mannitol is applied. This supplementary protection isolates the omeprazole from the outer coating layer that is designed to ensure gastro-protection of the active cores.
WO96/01624 in the name of ASTRA discloses a tableted dosage form comprised of individually enteric coated layered units of a core material comprising a benzimidazole ingredient. Said individually enteric coated layered units are mixed with tablet excipients and compressed together. Said tablet excipients are e.g. microcrystalline cellulose. The resulting tablet is said to withstand acidic environment.